The e4 allele of the apolipoprotein E gene (APOE) is a genetic risk factor for late onset Alzheimer's disease (AD). APOE-epsilon4 alone is neither necessary nor sufficient to cause AD. Other genetic and environmental factors are also likely to play a role in modifying the APOE-related risk of developing AD. Recently, studies have suggested an association of single nucleotide polymorphisms (SNPs) in the promoter region of APOE with increased risk for AD. These APOE SNPs were further demonstrated to modulate APOE expression. Thus, SNPs in both the promoter and non-coding regions of APOE may influence transcriptional level of APOE thereby adding to the risk in AD. The goal of this proposal is to identify APOE haplotypes and critical non-coding SNPs that influence APOE expression and AD risk as conferred by the APOE-epsilon4. A gene-based haplotype method will be developed to determine APOE haplotypes from each individual in our AD cases and controls sample. The APOE haplotype frequencies will be compared in AD cases vs. controls, and APOE-e4 allele status will be stratified (epsilon4 positive vs. epsilon4 negative) to assess the independence of the haplotypes in AD. Haplotypes, either over- or under-represented in AD, will be selected and subjected to expression studies. APOE expression levels will be evaluated by measuring mRNA levels in cells with different APOE haplotypes. Critical SNP alleles within these haplotypes that modulate APOE expression will be identified. The specific aims are to: 1. Construct APOE gene-based haplotypes from a large sample of sporadic AD cases and controls. 2. Analyze the association between APOE haplotypes and AD. 3. Establish association between APOE expression level and haplotypes. 4. Identify critical SNPs from candidate haplotypes that affect APOE expression.